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Molecular Pathways Regulating the Geometric Induction of Bone Formation
Published in Ugo Ripamonti, The Geometric Induction of Bone Formation, 2020
During osteoblast differentiation, the TGF-β isoforms signal via the canonical Smad2/3 pathway and non-classical TAK1-MMK-p38 pathways, whilst the BMPs signal through type I and II BMP and ALK2 receptor. Signal transduction is via Smads1/5/8 (Derynck and Zhang 2003). Signalling via the TGF-β and BMP pathways converges to activate the expression of the master transcriptional regulator RUNX2 (Grafe et al. 2018). However, there is considerable complexity in the pathways governing bone formation, and the BMP and TGF-β pathways exert their effects by cross-talk with several other pathways (reviewed in Guo and Wang 2009). The BMP pathway cross-reacts with components of the Wnt, Notch and fibroblast growth factor (FGF) pathways, whilst elements of the TGF-B pathway cross-react with the FGF, Wnt and the pituitary hormone (PTH) pathways. A further level of complexity is added by the activities of antagonists, such as Noggin, Chordin, Gremlin and Cerberus which control the activities of the growth factors (see Wu et al. 2016). The inclusion of the BMP inhibitor in these crucial experiments detailed in this chapter hints at the complexities of the signalling pathways controlling the induction of bone formation by the 7% HA/CC macroporous constructs in the Chacma baboon.
Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
In the cartilage anlage, in presumptive areas of synovial joint development, a prominent interzone can be discerned prior to overt differentiation. In fields of joint development, Wnt5, Wnt14 (Wnt9a), and GDF5 cooperate to induce joint formation. Wnt14 is critical in determining the location of the joint in the developing skeleton; this requires the cooperation of GDF5. Under these signals, the interzone cells become flattened and change from expressing type II collagen to expressing type I collagen (Craig et al. 1987). Induction of the interzone cells is not completely understood and may have species variations (Francis-West et al. 1999). The interzone cells appear to selectively express Wnt14 (Hartmann and Tabin 2001) and act as a signaling center through expression of noggin and chordin for control of cavitation and production of the joint space (Koyama et al. 2007; Seemann et al. 2009). Noggin is critical for joint morphogenesis, as mice lacking noggin fail to produce joints (Brunet et al. 1998; Tylzanowski et al. 2006).
Dentin-Pulp Complex Regeneration
Published in Vincenzo Guarino, Marco Antonio Alvarez-Pérez, Current Advances in Oral and Craniofacial Tissue Engineering, 2020
Amaury Pozos-Guillén, Héctor Flores
In vivo and in vitro studies report that placement of exogenous growth factors, particularly TGF-β and Bone Morphogenetic Proteins (BMPs), on exposed pulps, have demonstrated the potential of these molecules to signal reparative dentinogenic events. In application of growth factors to exposed pulps in capping conditions, growth factors stimulated reparative responses, but the reparative dentin matrix secreted showed variable structure ranging from a tubular matrix like physiological dentin, to atubular osteodentin-like matrices (Rutherford et al. 1994; Nakashima 1994a; Hu et al. 1998). The TGF-β family of growth factors as well as different components of the matrix have been demonstrated as chemotactocos for mesenchymal cells and the migration of these cells to the sites of damage. TGF-β1 regulates a wide range of cellular activities, such as cell migration, cell proliferation, cell differentiation and extracellular matrix (ECM) synthesis. TGF-β1 has been shown to increase cell proliferation and production of the ECM in dental pulp tissue culture, and promotes odontoblastic differentiation of dental pulp cells (Massagué et al. 2000; Verrecchia and Mauviel 2002; Lambert et al. 2011). BMPs include a subgroup of the TGF-β superfamily and are involved in biological activities such as cell proliferation, differentiation and apoptosis. BMPs have osteoinductive and chondrogenic effects. More than 20 BMPs have been identified and characterized; its activity is regulated by the antagonists of BMPs such as noggin and chordin; this modulation has a critical role in tooth development (Chen et al. 2004). BMP2, BMP4, BMP7 and BMP 11 are of clinical significance due to their role in inducing mineralization. Bovine dental pulp cells treated with BMP2 and BMP4 differentiate into pre-odontoblasts (Nakashima et al. 1994b). Dentin sialophosphoprotein expression and odontoblastic differentiation are regulated via BMP2. It also stimulates the differentiation of dental pulp stem/progenitor cells into odontoblasts in vivo and in vitro (Iohara et al. 2004; Chen et al. 2008). BMP7 or osteogenic protein-1, promotes dentin formation when placed over amputated dental pulp in animal models (Rutherford et al. 1994; Rutherford and Gu 2000; Six et al. 2002). Dental pulp cells transfected with BMP11 or GDF11, promotes mineralization. Dentin matrix protein 1, ALP, DSPP, enamelysin and phosphate-regulating gene are expressed in BMP11-transfected cells. Transplantation of BMP11-transfected cell pellets induces formation of dentin-like tissue on amputated dental pulp in an animal model (Nakashima et al. 2004).
Emerging therapeutic targets for NASH: key innovations at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
Bone-morphogenetic proteins (BMPs) are cytokines, belonging to the TGFβ family of proteins, discovered as regulators of bone and cartilage formation, embryonic development [82,83], and an array of other cellular functions. Regulation and signaling of BMPs is complex and is described in further detail elsewhere [84]. BMPs bind to a hetero-tetrameric receptor complex comprised of Type I and Type II receptors, which upon BMP binding initiate canonical and non-canonical signaling cascades. The canonical signaling pathway involves the phosphorylation and subsequent activation of Smad 1, 5 and 8 which act as transcription factors, counteracting the transcriptional regulatory properties of Smad2/3, and the non-canonical signaling pathway involves Rho-, PKC- and PI3K/AKT-signaling pathways [84]. The activity of BMPs is regulated by several extracellular soluble BMP inhibitors and antagonists like Follistatin, Noggin, Chordin or Gremlin-1 with varying specificity for different BMPs [84].
Different cellular mechanisms from low- and high-dose zinc oxide nanoparticles-induced heart tube malformation during embryogenesis
Published in Nanotoxicology, 2022
Mengwei Wang, Ping Zhang, Zeyu Li, Yu Yan, Xin Cheng, Guang Wang, Xuesong Yang
From the aforementioned discussion, we can see that low-dose ZnO NPs exposure could cause a certain percentage of malformation phenotypes but did not induce a large amount of cell death simultaneously (Figure 6A). Instead of vast precardiac cell death, the low-dose ZnO NPs exposure mainly caused the cellular responses that involved in an alteration in the expressions of key genes (Wnt3a, FGF8, NKX2.5, GATA4, and BMP2) related to early cardiogenesis (Figure 6). On the whole, cardiogenic induction is spatiotemporally determined by a battery of cardiogenic transcription factors (e.g. BMP2, FGF8 and Shh) and the combination of inducers/inhibitors of cardiac mesoderm-derived signaling (e.g. Chordin, Noggin, Wnt1,3,8) (Brand 2003). Hence, it is suggested that the various phenotypes of heart tube formations induced by low-dose ZnO NPs might be partially due to the aberrant expressions of these cardiogenic genes. Specifically, the normal concomitant migration and differentiation of prospective cardiac progenitors on their way toward the destination in two bilateral heart fields are indispensable for the embryonic stage of cardiogenesis (Wittig and Munsterberg 2016; Yue et al. 2008). The hallmark of EMT is the up-regulation of N-cadherin followed by the down-regulation of E-cadherin, while targeting β-catenin and vinculin complex formation through enhanced levels of E-cadherin could be a potential endpoint of EMT (Pal et al. 2019). This process is also regulated by RhoA activation (Loh et al. 2019). In this study, ZnO NPs inhibited the migration of cardiac progenitors by interfering with cell-cell junction molecule expressions including ZO-1, P120, N-cadherin, and RohA and reducing cell migration ability (Supplementary Figure 10).